The present disclosure relates generally to compounds that inhibit protein tyrosine phosphatases (PTPs). PTPs play an important role in the regulation of cellular growth and differentiation by serving as key regulatory components in the tyrosine phosphorylation-mediated signaling pathways. Defective or inappropriate regulation of PTPase activity leads to aberrant tyrosine phosphorylation, which contributes to the development of many human diseases including cancers and diabetes. For example, gene knockout studies in mice have identified PTP as a promising target for anti-diabetes/obesity drug discovery. Previous studies indicate that PTP-MEG2 (protein tyrosine phosphatase, non-receptor type 9, an intracellular PTP containing an N-terminal Sec14 homology domain) is an antagonist of hepatic insulin signaling (Cho, et al., Cell Metab. 2006, 3, 367-378). Ectopic expression of PTP-MEG2 in HepG2 cells reduces insulin-stimulated insulin receptor (IR) phosphorylation at Tyr1162/1163, which is required for its kinase activity, while RNAi-mediated PTP-MEG2 knockdown enhances insulin action. Additionally, increased PTP-MEG2 expression in liver suppresses insulin signaling, whereas hepatic silencing of PTP-MEG2 improves insulin sensitivity in db/db diabetic mice.
Thus, specific and potent PTP inhibitors are valuable for both biological studies and pharmacological development. However, the highly conserved PTP active site (i.e. the pTyr-binding cleft) makes it extremely difficult to develop selective active site-directed inhibitors. Remarkably, pTyr alone is not sufficient for high-affinity binding and residues flanking pTyr also contribute to PTP substrate recognition (Zhang, Annu. Rev. Pharmacol. Toxicol. 2002, 42, 209-234). These findings indicate that there are subpockets adjacent to the PTP active site that can be targeted for inhibitor design. A known strategy for obtaining potent and selective PTP inhibitors is by tethering appropriately functionalized moieties to a non-hydrolyzable pTyr mimetic in order to engage both the active site and nearby peripheral binding pockets (Puius, et al., Proc. Natl. Acad. Sci. USA 1997, 94, 13420-13245). Phosphonodifluoromethyl phenylalanine (F2Pmp), a well-established non-hydrolyzable pTyr surrogate (Burke, et al., Biochem. Biophys. Res. Commun. 1994, 204, 129-134; and Chen, et al., Biochem. Biophys. Res. Commun. 1995, 216, 976-984), has been previously utilized to generate potent and selective PTP inhibitors (Shen, et al., J. Biol. Chem. 2001, 276, 47311-47319; Sun, et al., J. Biol. Chem. 2003, 278, 12406-12414; and Zhang, et al., J. Am. Chem. Soc. 2009, 131, 13072-13079).
Thus, there is a need for more potent and selective inhibitors for individual members of the PTP enzyme family. As provided herein, the present disclosure provides novel PTP inhibitor compounds synthesized from F2Pmp.